PT84983B - PROCESS FOR THE PREPARATION OF PENEM DERIVATIVES - Google Patents

Abstract

An efficient process for converting readily available 4-acetoxy-2-azetidinones to allyl 2-thioxopenam3-carboxylates, intermediates useful for the synthesis of penem antibiotics.

Description

DESCRIPTIVE MEMORY

The present invention relates to an improved process for the preparation of certain intermediates useful for the synthesis of compounds of formula

where R is hydrogen or

and R | it is a conventional hydroxy protecting group particularly t-butyldimethylsilyl. These compounds are useful as intermediates for the synthesis of valuable antibiotics and / or beta-lactamase inhibitors such as SCH 29482:

^ ^S \ X ^SC 2 ^H 5

H ^X co ₂ h

See Ganguly et al., J. Antimicrob. Chemotherapy. 9, Supplement C, pp. 1-6 (1982).

intermediate compound in which R is 1- (t-butyl-dimethyl-silyloxy) ethyl is a known compound (Leanza et al., Tetrahedron 39, pp. 2505-2513 (1983)).

The present intermediates convert to known valuable compounds (eg Ganguly et al., Loc. Cit., Hamanaka, European Patent Application 130.025; Daniéis et al., J. Chem. Soc., Chem. Commun. 1982, pp. 1119-1120; Tanaka et al., Ibid., Pp. 713-714) according to known methods of alkylation (eg Leanza et al., Loc. Cit.), Removal of alkyl protecting groups (eg, Ganguly et al., loc. cit .; Girijavallabhan et al., Tetrahedron Lett. 22, pp. 3485-348I (1981), Jeffrey et al., J. Org. Chem. 47, pp. 587-590 (1982)) , and removal of the silyl protecting groups (eg, Hayashi et al., Chem. Pharm. Bull. 29, pp. 3158-3172 (1981)).

The precursors of interest for the above compounds of formula I are the 4-acetoxy-2-azetidinones of formula

H n * OCOCHW- <

l ^H --- (A)

---- NH

The one where R has the previous meaning. In reality, the racemic compound in which R is H is now commercially available (see Mi2

ckel, Aldrichimica Minutes 18 pp. 95-99 (1985)), and the chiral compound in which R is 1- (t-butyl-dimethyl-silyl-oxy) ethyl is easily obtained from 6-amino-penicillanic acid by the process of Leanza and others , loc. cit.

According to the present invention, compounds of formula A are reacted first with sodium t-butyltrithiocarbonate and then with allyl glyoxylate to

and then with SOX ₂ (where X = Cl or Br) to provide a compound of the formula

- (III)

The present invention addresses specifically the step of the unconventional process of converting a compound of formula III into a compound of formula II

--- (II) which is characterized by:

(a) contacting said compound of formula III with sodium iodide in a solvent inert to the reaction medium at a

X temperature between 0 and 359 C; or (b) heating said compound of formula III in a solvent inert to the reaction medium, at a temperature of between 25 and 80 ° C, when X is bromine, or between 60-1009 ° C when X is chlorine. The preferred solvent is acetonitrile with or without the addition of an inert solvent to the reaction medium.

As used herein, the term solvent inert to the reaction medium refers to a solvent that does not interact with intermediate reagents or final products so as not to adversely affect yield. It should be noted that in the reaction in the previous paragraph, solvents that trap carbon dioxide, such as acetonitrile, which can have a favorable effect on yield by reducing side reactions, will also be considered inert to the reaction medium according to this definition.

The present invention also focuses on the unconventional process step of converting a compound of formula II into a compound of formula I, characterized in that said compound II is contacted with an equivalent of a weakly nucleophilic strong anhydrous base, in a solvent reaction inert; and also cover intermediate compounds of formula II per se.

In all cases, R has the meaning previously given to the compound of formula I. The preferred values for R are hydrogen (with compounds A, Β, III, II and I in racemic form), and 1- (t- butyl-dimethyl-silyl-oxy) ethyl (with the corresponding compounds in optically active form.)

A strong weakly nucleophilic base refers to bases such as alkali metal hydride, t-butoxide or hexa-methyl-di-silazide with sufficient power to carry out the desired reaction with little or no unwanted interaction with the allylic ester groups. or beta-lactam. The reaction is optionally carried out in the presence of triphenylphosphine.

The present invention is easily accomplished. The starting materials of formula II are prepared by conventional methods as exemplified in the preparations detailed below.

Since X is chlorine or bromine, the conversion of compound III to compound II is carried out by dissolving compound III in an inert reaction solvent, preferably acetonitrile at a temperature between 0 and 359 C, conveniently at an ambient temperature between 18 and 259 C, by contacting the solution with the iodide salt, conveniently sodium iodide, and allowing the reaction to proceed until complete (approximately between 0.3 and 1 hour at room temperature when using a stoichiometric amount of iodide ).

Alternatively, compound III can simply be heated in an inert reaction solvent, preferably acetonitrile, with or without the presence of more inert reaction solvent, at a temperature between 25 and 809 C when X is bromine and between 60 and 1009 C when X is chlorine. In any case, the product is isolated and purified by conventional methods, for example, dilution with an organic solvent and miscible in water, removal of salts and other impurities by extraction with water, and evaporation, being the chromatography column silica gel optional.

compound II becomes the compos. to I in an inert reaction solvent in the presence of an equivalent of a weakly strong nucleophilic anhydrous base. The temperature is not very critical but will preferably be between -509 and 109 ° C to minimize side reactions; most preferred are temperatures in the middle of the upper portion of the range, that is, close to 09 ° C. The solvent is not critical, although polar ethers such as tetrahydro furan are preferred. The reaction is preferably carried out in the presence of a triphenyl phosphine equivalent, in which case the sulfur released in the reaction ends in the form of triphenyl phosphine sulphite. The preferred weakly nucleophilic strong bases, as defined above are sodium hydride, potassium t-butoxide, lithium t-butoxide and lithium hexamethyl-silazide.

As mentioned above, the present compounds of formula I are converted into valuable and well-known compounds by conventional processes well known in the art. specialty of beta-lactam preparation.

ί

examples.

EXAMPLE 1

Allyl 4-thioxo-1-aza-3,5-di-thia-bicyclo- (4.2.0) octan-8-one-2-carboxylate

Process A

To a solution of product from preparation 4 (0.04 g, 0.11 mmol) in 2 ml of CHg CN was added NAI (17.9 mg). After stirring for 30 minutes, the reaction mixture was removed to an oil which was partitioned between 2 ml of water and 2 ml of CH ₂ C12. The CH ₂ Cl ₂ layer was separated and chromatographed on silica gel using 1: 2 ethyl acetate: hexane as the eluent to provide the title product as an oil, 9.7 mg; tlc Rf 0.3 (1: 2 ethyl acetate: hexane); ¹ H-nmr (CDClg) delta (ppm) 5.98-5.82 (m, 1H), 5.86 (s, 1H), 5.49 (dd, J = 4.5, 1.7, 1H), 5.41-5.31 (m, 2H), 4.70 (d, J = 5.9, 2H), 3.83 (dd, J = 15.6, 4.5, 1H), 3.25 (dd, J = 15.5, 1.8, 1H).

Process B

For 16 hours, it was refluxed in an oil bath at 90 ° C of a solution of the product of preparation 4 (515 mg; 1.4 mmol) in 14 ml of CH 2 CN, and then the mixture was removed and chromatographed. residue on silica gel with hexane:: 5: 2 ethyl acetate as eluent to provide the title product; 253 mg; tlc Rf according to process A above.

Process C

The product of preparation 5 (9.3 mg; 0.023 mmol) was heated in 1 ml of CH2 CN at 60-629 C for 40 minutes, then removed and extracted with ethyl acetate and finally with CH ₂ Cl ₂ to provide a quantity of the title product, identical to the product of process A.

_ ç _

EXAMPLE 2 Allyl r-5H-3-toxo-1-aza-4-thio-bicyclo (3.2.0) -heptan-7-one-c-2-carboxylate or 2-thioxy-penam-3-carboxylate

Process A

Sodium hydride (60% in mineral oil, 60.3 mg; 1.5 mmol) was suspended in 1 ml of tetrahydrofuran. The title product from the previous example (16.7 mg; 0.06 mmol) dissolved in 1 ml of tetrahydrofuran was added to the suspension over 1-2 minutes. A transient purple color was observed, followed by a yellow color and gas release.

I After 10 minutes, triphenylphosphine (18.1 mg;

0.069 mmol). After a further 10 minutes, the reaction mixture was poured into 3 ml of saturated NH4 Cl and extracted twice with 5 ml of CH2 C12. The organic layers were combined, dried over NA2 SO4 and removed. to provide a mixture of the title product, triphenyl phosphine, triphenyl phosphine sulfite, and mineral oil, 42.7 mg, separated by chromatography on silica gel with ethyl acetate: hexane 1: 2 as an eluent to provide the title product as an oil, 1.3 mg, ^ H-nmr (CDCl ₃ ) delta (ppm) 5.90 (dd, J = 1.6, 4.2, 1H at position 5), 5.95-5.84 (m, 1H), 5.36 (s, 1H at position 2), 5.40-5.26 (m, 2H), 4.69 (dd, J = 1.4, 5.7, 2H), 3.90 (dd, J = 4.2, 16.4, 1H), 3.48 (dd, J = 1.7, 16.4, 1H); tlc Rf 0.2 (1: 2 ethyl acetate: hexane).

Process B

The title product from the previous example (35.67 mg; 0.13 mmol) in 0.5 ml of tetrahydrofuran was added to a mass of sodium hydride (5.1 mg; 0.13 mmol) and 3.4 mg of mineral oil in 0.5 ml of tetrahydrofuran while stirring at -309 C. After 30 minutes, the reaction mixture was quenched and the title product was isolated according to procedure A above .

Process C

Triphenylphosphine (52.7 • mg; 0.20 mmol) was placed under nitrogen. Did the title product of ê, dissolve. / · - ·· ^ jrrn? ⁵ · —'ί-χt> r ,, _ 2à jieeaiBis ** · / 'previous example (54.76 mg; 0.20 mmol) in 1 ml of tetrahydrofuran, was added to the triphenylphosphine with a syringe and the mixture was cooled to 0 to 59 ° C. Then added. was slowly added with a potassium t-butoxide syringe (1

ml of 0.20 M in freshly prepared tetrahydrofuran in a dry box). After 10 minutes, the mixture was quenched with 5 ml of saturated NH4 Cl, extracted twice with 5 ml of CH ₂ Cl ₂ / dried over NA ₂ SO ₄ and removed to provide 94 mg of product crude which was chromatographed on silica gel with 1: 2 ethyl acetate: hexane as eluent. The resulting partially purified product was extracted with 1 ml of isotropyl ether, the solid by-product was recovered by filtration (18 mg), and the title product (28 mg) was recovered from the mother liquor by chromatography on silica gel.

EXAMPLE 3

6R, 7S-4-thioxo-7- (1R-1- (t-butyl-dimethyl-silyl-oxy) ethyl) -l-aza-3,5-di-thio-bicycle (4.2.0) -octan- Allyl 8-one-2-carboxylate

Process A

The 1: 1 title diastereomeric product of preparation 8 (30.3 mg, 0.057 mmol) was refluxed in 7 ml of CH2 CN for 17 hours, cooled, removed and chromatographed on a gel. silica with ethyl acetate: hexane 1: 6 as eluent to provide the title product as an oil, 19.5 mg; tlc Rf 0.4 (1: 5 ethyl acetate: hexane); ^ H-nmr (CDCl ^) delta (ppm) 5.95-5.82 (m, 1H), 5.82 (s, 1H), 5.48 (d, J = 1.6, 1H), 5.40-5.30 (m, 2H), 4.71- 4.67 (m, 2H), 4.36-4.28 (m, 1H), 3.43 (dd, J = 4.6, 1.7, 1H), 1.29 (d, J = 6.2, 3H), 0.86 (s, 9H), 0.09 (s , 3H), 0.07 (s, 3H).

Process B

The dj product was completely dried. astereomeric 1: 1 in title 8 of preparation 8 (1.0 g; 1.90 mmol) by removal and extraction twice with dry benzene, and finally dried under intense vacuum for 1 hour. CH ₃ CN _ was added to _

4: ΐ?:. ·· ..., J - · ·.

HPLC grade (0.01% H ₂ 0, 95 ml) and 2.5 cc molecular filters and the mixture was refluxed for 16 hours, cooled, filtered, removed and chromatographed with 1: 6 ethyl acetate: hexane as eluent to provide 0.457 g of the title product; tlc Rf 0.5 (1: 6 ethyl acetate: hexane); ΙΗ-nmr identical to process A immediately preceding.

Process C

The product of preparation 9 was completely extracted with 5 ml of CH2 CN and heated to 479 ° C for 2 hours and then to 629 ° C for 1 hour. The reaction mixture was removed and the residue was chromatographed on silica gel, eluting first with ethyl acetate: hexane 1: 4 and then with ethyl acetate: hexane 1: 2. The desired product was in the fractions which were eluted with the eluent in the proportion 1: 4, 56 mg tlc Rf 0.75 (ethyl acetate: hexane 1: 2). The latter fractions provided the 49 mg, tlc Rf 0.3 (ethyl acetate: hexane 1: 2) desylated product, indicating that better yields can be achieved by maintaining better anhydrous conditions.

EXAMPLE 4

2S, 5R, 6S-3-thioxo-6- (1R- (t-butyl-dimethyl-silyl-oxy) ethyl) -1-aza-4-thio-bicycle (3.2.0) heptan-7-one-2 allyl-carboxylate or 3S, 5R, 6S-6- (IR- (t-butyl-dimethyl-silyl-oxy) ethyl) -2-thioxy-penam-3-carboxylate

Process A

The product of the preceding example (12.5 mg; 0.029 mmol) was dissolved in 1 ml of tetrahydrofuran sot N ₂ and cooled to 09 ° C. Potassium t-butoxide (0.078 ml of 0.385 M in tetrahydrofuran). After 3 minutes, the mixture was quenched with an equal volume of saturated NH4 Cl, then diluted with 4 ml of CH ₂ Cl ₂ and 4 ml of H ₂ 0. If the aqueous layer was stopped and extracted with 4 ml of fresh CH ₂ Cl ₂ . The organic layers were combined, dried over NA ₂ SO ₄ and removed to provide the title product as q -

an oil, 8.2 mg; ^ H-nmr (CDCl ^) delta (ppm) 5.96-5.80 (m, 1H), 5.86 (d, J = 1.2, 1H), 5.32 (s, 1H), 5.37-5.25 (m, 2H), 4.67- 4.64 (m, 2H), 4.40-4.31 (m, 1H), 3.63 (dd, J = 4.0, 1.7, 1H), 1.28 (d, J = 6.2, 3H), 0.87 (s, 9H), 0.08 (s , 3H), 0.07 (s, 3H); identical to the known material previously identified as a low melting solid, by Leanza and others, previously mentioned.

Process B

T-butanol (1 ml, freshly distilled from CaH) was combined with 35.4 ml of dry tetrahydrofuran and cooled to -789 C. N-butyl lithium (6.63 ml of 1.6 M in hexane) and the mixture was heated to 9 ° C to provide a 0.3 M solution of lithium t-butoxide. Dissol. the product of the preceding example (59 mg; 0.136 mmol) was seen in

4.5 ml of dry tetrahydrofuran and cooled to 09 ° C. With a syringe, lithium t-butoxide (0.454 ml of the above 0.3 M solution, 0.136 mmol) was added over 2 minutes. After stirring for a further 2 minutes, the reaction was quenched with an equal volume of saturated NH4 Cl and subsequently isolated according to process A immediately above. The resulting product was chromatographed on silica gel using 1:49 ethyl acetate: hexane as the eluant to provide the purified title product, 33 mg; identical to the product of process A immediately preceding.

Process C

The product of the previous example (34 mg; 0.079 mmol) was dissolved in 2.6 ml of tetrahydrofuran, stirred and cooled to 09 ° C under N ₂ · Hexamethyl-di was added with a syringe -lithium silazide (0.085 ml of a 1 M solution in tetrahydrofuran, 0.085 mmol). After 20 minutes of stirring the reaction mixture was transferred to 3 ml of saturated Cl and extracted with 6 ml of CH ₂ Cl ₂ · The organic layer was separated, dried and removed to an oil (36 mg). The latter was chromatographed on silica gel to provide the purified title product, 19 mg, identical to the product of ί n

processes A and B immediately preceding.

EXAMPLE 5

6S- (IR- (t-butyl-dimethyl-silyl-oxy) ethyl) -2-ethyl-thio-2-penem-3-car ·· boxylate

The product of the preceding example (8.2 mg; 0.020 inmol), diisopropyl ethyl amine (Hunig's base; 0.020 ml; 0.115 mmol) and ethyl iodide (0.032 ml; 0.4 C mmol) were combined under at 09 C in 1 ml of tetrahydrofuran, allowed to warm to room temperature, stir for 14 hours, remove and chromatograph the residue on silica gel with ethyloxhexane acetate 1: 6 as an eluent to provide the title product as a white solid, 2.9 mg; tlc Rf 0.4 (1: 5 ethyl acetate: hexane). ^ H-nmr (CDCl ^) delta (ppm) 5.90 (m, 1H), 5.58 (s, 1H), 5.38 (bd, J = 17.2, 1H), 5.20 (bd, J = = 10.5, 1H), 4.70 (m, 2H), 4.21 (m, 1H), 3.65 (dd, J = 5.0, 1.6, 1H), 2.96 (m, 2H), 1.35 (t, J = 7.4, 3H), 1.23 (d, J = 6.2, 3H), 0.85 (s, 9H), 0.06 (s, 6H).

The title product was distilled by treatment with tetra-butyl ammonium fluoride in tetrahydrofuran in the presence of acetic acid according to the method of Hayashi et al., Chem. Pharm. Bull. 29, pp. 3158-3172 (1981) to provide the known 6S- (1R-1-hydroxy-ethyl) -2-ethyl-thio-2-penem-3-carboxylate, previously used as an intermediate in the synthesis of 6S- ( 1R-1-hydroxy-ethyl) -2-ethyl-thio-2-penem-3-carboxylic (Sch 29482) by Ganguly et al., J. Antimicrob. Chemotherapy, supplement C, pp. 1-6, (1982).

Preparation 1

4- (t-butyl-thio (tlo-carbonyl) thio) -2-azetidinone

Process A

4-Acetoxy-2-azetidinone (0.44 g, 3.4 mmol) and sodium t-butyl-tri-thio-carbonate (0.64 g;

, 3.4 mmol) in 15 ml of ethanol and stirred under N ₂ for 20 minutes. The reaction mixture was removed and the residue was partitioned

between 5 ml of H ₂ 0 and 5 ml of CH ₂ CI2. The organic layer was separated, washed once with 5 ml of H ₂ O and once with 5 ml of a saturated saline solution, dried over Na ₂ SO ₄ , removed as a semi-oil solid (0.59 g) and combined with 0.38 g of a similar product similarly prepared in 15 ml of acetone from 0.31 g (2.4 mmol) of azetidinone. The combined crude products were chromatographed on silica gel, using hexane: 1: 1 CH ₂ Cl ₂ 1: 1 containing 1% methanol and finally 2% methanol, to provide the solid title product, 0.95 g; tlc Rf 0.6 (1:19 methanol: CH ₂ C _{1 2} ); ^ H-nmr (CDClg) delta (ppm) 6.62 (bs, 1H), 5.45 (dd, J = 5.3, 2.6, 1H), 3.43 (ddd, J = 15.3, 5.3, 2.0, 1H), 2.99 (ddd, J = 15.3, 2.6, 1.3, 1H), 1.61 (s, 9H).

Process B

4-Acetoxy-2-azetidinone (0.21 g, 1.63 mmol) and sodium t-butyl-tri-thio-carbonate (0.286 g, 1.5 mmol) were dissolved in 16 ml of H ₂ O. The precipitation of the product started almost immediately. After 20 minutes, the title compound was collected by filtration and dried in an intense vacuum, 243 mg; Federal Police. 113-1169 C.

Preparation 2

Allyl Glyoxylate

Dialyl tartrate (17.9 g; 0.078 mmol) was dissolved in 389 ml and ether and cooled to 09 ° C. Solid periodic acid (35.46 g; 2 molar equivalents) was added and the mixture was stirred for 4 hours, then washed 3 times with 150 ml of saturated Na ₂ S ₂ , dried over Na ₂ SO ₄ and removed to provide the title product as an oil. , 8.27 g; tlc Rf 0.4 (3: 2 ethyl acetate: hexane).

Preparation 3

2-hydroxy-2- (4- (t-butyl-thio (thio-carbonyl) -thio) -2-azetidinon-1-yl) allyl acetate

Allyl glyoxylate (0.96 g; 8.4 mmol) and 4- (t-butyl-thio (thio-carbonyl) thio) -2-azetidinone (0.95 g; 4.0 mmol) were combined in 40 ml of benzene under N ₂ and re-flowed for 20 hours using Dean-Stark equipment loaded with type 4A molecular filters. Then more allyl glyoxylate (0.87 g, 7.7 mmol) was added and the reflux was maintained for 24 hours. Then the reaction mixture was removed as an oil which was chromatographed on silica gel with 2: 1 hexane: ethyl acetate as eluent to provide the purified title product, 1.00 g; tlc Rf 0.5 (1: 1 (hexane: ethyl acetate 1: 1); * 'H-nmr (CDCl ^) delta (ppm) 5.95 and 5.84 (2dd, J = = 5.4, 2.7 and J = 5.3, 2.6, 1H), 6.01-5.82 (m, 1H), 5.48 and 5.27 (2d, J = 8.4 and 7.8, 1H), 5.41-5.28 (m, 2H), 4.75 and 4.72-4.66 (d, J = 6.0 in, 2H ), 4.01 and 3.87 (2d, J = 8.4 and 7.9, 1H), 3.58 and 3.57 (2dd, J = 15.7, 5.4 and 15.6, 5.5, 1H), 3.14 and 3.10 (2dd, J = 15.6, 2.7 and 15.7, 2.6, 1H), 1.61 (s, 9H), which reflects 2 racemic pairs.

This preparation was repeated with 6.83 g (0.029 mmol) of azetidinone and 6.63 g (2 molar equivalents) of glyoxylate, and refluxing was carried out for 48 hours without further addition of glyoxylate and chromatographed with acetate. ethyl: hexane 1: 2 as eluant to provide 10.2 g of the title product having the same physical properties as indicated immediately behind.

Preparation 4

2-chloro-2- (4- (t-butyl-thio (thio-carbonyl) -thio) -2-azetidinon-1-yl) allyl acetate

Process A

The product of the previous preparation (0.10 g, 0.29 mmol) and triethylamine (0.2 ml; 1.4 mmol) was dissolved in 2 ml of CH ₂ Cl ₂ and cooled to 09 C. mesyl dye (0.033 ml; 0.43 mmol) and the mixture was stirred at 09 ° C for 20 minutes, then washed with 2 ml H ₂ O, 2 ml saturated NaHCOg and 2 ml saturated NaCl, dried over Na ₂ • SO ^ and removed as an oil, 0.10 g, which is chromatographed. silica gel with ethyl acetate: hexane 1: 4 as eluent -

te to provide the title racemic diastereomeric products in a slightly greater proportion than 1 to 1, 0.08 g; tlc Rf 0.7 (1:19 CH ₂ OH: CH ₂ C _{1 2} ), 0.6 (2: 5 ethyl acetate: hexane); ^ H-nmr (CDCl ^) delta (ppm), which reflects two racemic pairs, 6.09 and 6.02 (2s, 1H), 6.04 and 5.98 (2dd, J = 5.3, 2.6 and J = = 5.5, 2.7, 1H) , 6.00-5.84 (m, 1H), 5.41-5.28 (m, 2H), 4.75-4.67 (m, 2H), 3.68 (dd, J = 16.1, 5.6, 1H), 3.18 and 3.14 (2dd, J = 16.1 ,

2.9 and J = 16.0, 2.6, 1H), 1.61 (s, 9H); ir 1805, 1760 cm ¹ .

Process B

The product of the preparation was dissolved | previous reaction (1.0 g, 2.86 mmol) in 15 ml of dry tetrahydrofuran, stirred under N ₂ and cooled to 09 C. Triethylamine (0.479 ml; 1.2 molar equivalents) was added and then SOCI2 (0.251 ml; 1.2 molar equivalents), with the last addition lasting approximately 5 minutes. After stirring for an additional 35 minutes at 09 ° C, the reaction mixture was poured into 20 ml of saturated NaHCO3. Most of the tetrahydrofuran was removed in vacuo and the aqueous residue was extracted twice with 30 ml of CH ₂ Cl ₂ . The CH ₂ Cl ₂ extracts were washed with a saturated saline solution, dried over Na ₂ SO ₄ , and the residue was removed and chromatographed on silica gel using ethyl acetate: hexane 1: 3 as eluent, 0.756 g; identical to the product of process A above.

Preparation 5

2-bromo-2- (4- (t-butyl-thio (thio-carbonyl) -thio) -2-azetidinon-1-yl) allyl acetate

The product of preparation 3 (0.135 g, 0.386 mmol) was dissolved in 4 ml of tetrahydrofuran and triethylamine (0.22 ml; 0.156 g, 1.54 mmol) was added. The mixture was cooled to 09 ° C and then SOBr ₂ (0.060 ml; 0.16 g; 0.77 mmol) was added. After stirring for 1.5 hours at 09 ° C, the reaction mixture was diluted with 8 ml of ethyl acetate, washed twice with 6 ml of saturated NaHCO3, once with 6 ml of. H ₂ O and once with 6 ml of a saturated saline solution, it was dried over Na ₂ SO ₄ and removed as an oil (0.168 g) containing 14 -

the title product. The latter was used without further purification in the next processing. ^x H-nmr (CDCl3) delta (ppm] 6.23-5.80 (m, 3H), 5.40-5.20 (m, 2H), 4.80-4.58 (m, 2H), 3.72-3.5 (m, 1H), 3.20- 3.00 (m, 1H), 1.60 (s, 9H).

Preparation 6

3S, 4R-4- (t-butyl-thio (thio-carbonyl1) thio) -3- (1R-1- (t-buti1-dimethyl · -silyl-oxy) ethyl) -2-azetidinone

3R, 4R-4-acetoxy-3- (1R-1- (t-butyl-dimethyl-silyl-oxy) ethyl) -2-azetidinone (5 g, 0.0174 mmol) was dissolved in 150 ml of absolute ethanol and cooled to 09 C. Then carbon disulfide (0.523 ml; 0.0087 | mmol) was added and then t-butyl tri-thio-carbonate (3.28 g; 0.0174 mmol in 50 ml of After stirring for 45 minutes, the reaction mixture was removed, the residue was extracted with 100 ml of ethyl acetate, washed once with 100 ml of O and once with 100 ml of an saline, dried (Na £SO ^) and removed as a pasty solid, dried in an intense vacuum, massed in a minimum amount of hexane at 09 ° C and filtered to providing a first crop of the title product, 3.60 g The mother liquor was collected and mashed in a minimum amount of hexane to provide a second crop of equally pure title product, 0.49 g; tlc Rf 0.6 (1: 2 ethyl acetate: hexane); ^ H-nmr (CDClg) delta (ppm) 6.57 (bs, 1H), 5.58 (d, J = 2.6, 1H), 4.28 (m, 1H), 3.20 (m, 1H), 1.63 (s, 9H), 1.20 (d, J = 6.3, 3H), 0.88 (s, 9H), 0.07 (s, 6H).

Preparation 7

2R-e 2S-2-hydroxy-2- (3S, 4R-4- (t-butyl-thio- (thio-carbonyl) thio) -3- (1R-1- (t-butyl-dimethyl-silyl-oxy) ) ethyl) -2-azetidinon-1-yl) allyl acetate

Using the method of preparation 3, with ethyl acetate: hexane 1: 5 as eluent for chromatography, the product of the preceding preparation (86.4 mg; 0.20 mmol) was converted into the present title product. 21.9 mg of less polar diastereomer was obtained; tlc Rf 0.5 (1: 2 ethyl acetate:

* ι • hexane); H-nmr (CDCl3) delta (ppm) 6.14 (d, J = 3.0, 1H), 5.89

(m, 1Η), 5.49 (bs, 1H), 5.30 (m, 2H), 4.63 (m, 2H), 4.26 (m, 1¾ 3.34 (dd, J = 4.3, 3.0, 1H), 1.62 (s, 9H ), 1.19 (d, J = 6.0, 3H), 0.85 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 17.6 mg of mixed fractions; and 57.1 mg of more polar diastereomer; tlc Rf 0.45 (1: 2 ethyl acetate: hexane); H-nmr (CDCl ₃ ) delta (ppm) 6.06 (d, J = 2.7, 1H), 5.92 (m, 1H), 5.30 (m, 2H), 5.18 ( s, 1H), 4.73 (m, 2H), 4.23 (m, 1H), 3.29 (m, 1H), 1.61 (s, 9H), 1.21 (d, J = 6.1, 3H), 0.85 (s, 9H) , 0.05 (s, 3H), 0.03 (s, 3H).

Preparation 8

2R-e 2S-2-chloro-2- (3S, 4R-4- (t-butyl-thio (thio-carbonyl) thio) -3- (1R-1- (t-butyl-dimethyl-silyl-oxy) ethyl) -2-azetidinon-1-yl) allyl acetate 1: 1

Both diastereoisomeric products of the preceding preparation provided a similar mixture of the title products present. The most polar product of the preceding preparation (57.1 mg; 0.11 mmol) and triethylamine (0.062 ml; 0.45 mmol) were dissolved in tetrahydrofuran (3 ml) at 09 C. It was added with a syringe , SOCI2 (0.016 ml; 0.22 mmol). After 45 minutes, the reaction mixture was quenched with an equal volume of saturated NaHCO ₃ (note: gas evolution). The tempered mixture was extracted 3 times with 5 ml of CI2 and the organic layers were combined, dried over Na2 SO4 and removed to provide the title crude product as an oil, 56.8 mg. ; ^ H-nmr indicated some predominance of a diastereomer. The less polar isomer (21.9 mg; 0.043 mmol) was converted by an identical process into a mixture of similar crude products, 24.3 mg; ^ H-nmr indicated some predominance of the other diastereomer. The two crude products were combined and chromatography on silica gel was performed to provide the purified 1: 1 title product as an oil, 56.2 mg; tlc Rf 0.4 (1: 6 ethyl acetate: hexane); ^ H-nmr (CDC1 ₃ ) delta (ppm), which reflects a 1: 1 mixture of diastereomeric products, 6.40 and 6.30 (2d, J = 3.1 and d, J = 2.8, 1H), 6.11 and 5.89 (2s, 1H ), 6.00-5.85 (m, 1H), 5.42-5.27 (m, 2H), 4.72 and 4.65 (d, J = 5.9 and bd, J = 6, 2H), 4.32-4.23 (m, 1H), 3.42- 3.36 (m, 1H), 1.64 (s, 9H), 1.24 and 1.22 (d, J = 6.2 and d, J = 6.2, 3H), 0.88 and 0.86 (2s, 9H), 0.08 and 0.07 (2s,

- IS -

3Η), 0.06 and 0.05 (2s, 3H).

Preparation 9

2R-e 2S-2-bromo-2- (3S, 4R-4- (t-butyl-thio (thio-carbonyl) thio) -3- (1R-1- (t-butyl-dimethyl-silyl-oxy) ethyl) -2-azetidinon-1-yl) allyl acetate 1; 1

The product of preparation 7 (0.261 g, 0.512 mmol) was dissolved in 5 ml of dry tetrahydrofuran, cooled to -109 ° C, and then triethylamine (0.10 ml; 0.717 mmol) and SOBr _{2 were added.} (0.048 ml; 0.615 mmol). After 15 minutes at -109 C the mixture was poured into 5 ml CH ₂ Cl ₂ and 5 ml H ₂ O. The organic layer was separated, washed with water and saturated saline, dried over Na ₂ SO4 and removed to provide the title product as an oil; tlc Rf 0.28 and 0.32 (ethyl acetate: hexane 1: 4); ¹ H-nmr (CDClg) delta (ppm), which reflects a mixture of diastereoisomers, 6.32 (m, 1H), 6.20 and 6.07 (2s, 1H), 5.92-5.79 (m, 1H), 5.38-5.21 (m, 2H), 4.66-4.58 (m, 2H), 4.28-4.18 (m, 1H), 3.32 (m, 1H), 1.60 (s, 9H), 1.20-1.16 (m, 3H), 0.82 (s , 9H), 0.04 (s, 6H).

Claims (3)

Process for the preparation of a compound of formula in which R is hydrogen or and R 'is a conventional hydroxy protecting group, characterized in that it is a compound of formula --- (II) with an equivalent of a weakly strong nucleophilic anhydrous base in a solvent inert to the reaction medium. Process according to claim π n <S < Section 1, characterized in that the base is an alkali metal hydride, t-butoxide or hexamethyl-disilyazide, with or without the presence of triphenylphosphine. Process according to claim 2 characterized by R be hydrogen 4Process according to claim 2 characterized and R 'being t-butyl-dimethyl-silyl Process of formula (II) Ί Ω where R is hydrogen or e R 'is a conventional hydroxy protecting group, a compound of formula from i · --- (III) where R has the previous meaning and X is bromine or chlorine, characterized by: a) contacting said compound of formula III with sodium iodide in a solvent inert to the reaction medium at a temperature between 0-359 ° C, or b) heating said compound of formula III in an inert reaction solvent to a temperature between 25-809 C, quar, X is bromine or between 60-1009 C, when X is chlorine. - 6- Process according to section 5, characterized in that the solvent is acetonitrile and claims X be chlorc, Process according to the claim. section 6 characterized by R being hydrogen. 8. A process according to claim 6, characterized in that R is and R 'is t-butyl-dimethyl-silyl. The applicant declares that the first application for this patent was filed in the United States of America on June 2, 1986, under serial number 869,760.